Recently, an increasing number of medicines for treating conditions or diseases caused by cerebral dysfunction or cerebral organic disorders including the disturbance of consciousness, disturbance of memory, dysgnosia, and various types of dementia have been developed. Examples of such medicine include consciousness disturbance improving agents, psychotropic agents, anti-, dementia agents, and the like. The present inventors have already developed and disclosed carbamoyl pyrrolidone derivatives effective on senile dementia (EP-A-0304330) and tetrahydropyridine derivatives having psychotropic activity (EP-A-0445701).
The present inventors have made a continuous and intensive research with the purpose of developing novel compounds that have the following properties:
(1) a potent inhibitory activity against re-uptake of serotonin;
(2) a potent ability to suppress or inhibit the delayed necrosis of neuronal cells; and
(3) less or negligible enzyme induction. These properties will be explained in detail below.
(1) It has been well known that compounds capable of inhibiting the uptake of serotonin exhibit antidepressant activity (J. Clin. Psychiatry, 55: 3, March 1992). Thus, certain known antidepressants such as imipramine and amitriptyline are capable of inhibiting the amine pump responsible for the re-uptake of serotonin, which is released from the end of serotonergic nerves of central nervous system, by a neuroterminal, thereby increasing the serotonin concentration in the synaptic cleft.
(2) Cerebral ischemia is a local anemia of extremely high degree found in brain. Cerebral tissues placed under an ischemic condition often lead to dysfunction and, if the condition lasts, it would bring about the denature and necrosis of cells.
(3) In the clinical treatment with medicines, a gain in liver weight is observed following the administration of a medicine. This is due to the increase in the number of smooth surfaced endoplasmic reticulum (SER) in hepatic microsomes, which contains a series of enzymes participating in the drug metabolism. Thus, the administration of a medicine can stimulate the enzymatic activity which results in induction of enzymes responsible for the metabolism of drugs and shorten the term during which the medicine can exert its effect. The relationship between the enzyme induction and pharmacological and chemical structural features of a medicine has not been elucidated.